Genital lubricant with zinc salt, labelled as anti-viral agent

ABSTRACT

This invention relates to an article of manufacture including a genital lubricant containing a selected non-irritating, water-soluble zinc salt at an anti-viral concentration, within a package that is provided with a label indicating that the lubricant is effective as an anti-viral agent against at least one type of sexually transmitted virus (such as genital herpes viruses, human immunodeficiency viruses, hepatitis viruses, or papilloma viruses). One such lubricant includes a lubricant gel in a plastic-walled tubular package, for use with or without a condom; another such lubricant includes a condom lubricant, coated on a condom and sealed along with the condom inside a disposable plastic pouch. The zinc salt must be water-soluble and have substantial dissociation rates to release divalent zinc ions, and the lubricant must not cause genital irritation or other adverse effects, even if used repeatedly over a period of months or years. The zinc-containing lubricants described herein can reduce the risk that a previously uninfected person will become infected by sexually transmitted viruses, and the labelling information will help promote efficacy and slow the spread of incurable viruses.

This is a continuation-in-part of U.S. application Ser. No. 08/057,001,filed May 3, 1993, which issued as U.S. Pat. No. 5,499,377 on Mar. 12,1996, and of U.S. application Ser. No. 08/361,967, filed on Dec. 22,1994, now U.S. Pat. No. 5,599,651, which was a continuation-in-part ofU.S. application Ser. No. 08/056,480, filed on May 3, 1993, nowabandoned. Both Ser. No. 08/057,001 and Ser. No. 08/056,480 were acontinuations-in-part of U.S. application Ser. No. 07/737,169, filed onJul. 29, 1991, which issued as U.S. Pat. No. 5,208,031 on May 4, 1993.That application was a continuation-in-part of application Ser. No.07/528,495 filed on May 25, 1990, now abandoned, which was acontinuation-in-part of application Ser. No. 07/362,058, filed on Jun.6, 1989, also abandoned.

BACKGROUND OF THE INVENTION

This invention is in the fields of biochemistry, pharmacology, andanti-viral agents.

There is a major need for methods to prevent the spread of viruses thatare transmitted through sexual contact, including genital herpes viruses(herpes simplex virus type 2, HSV-2), the human immunodeficiency virus(HIV, the causative agent of AIDS), hepatitis viruses, and papillomaviruses. Extensive information on each of these viruses is contained innumerous medical books and articles; for example, Mindel 1989 offers agood overview of herpes viruses, while the October 1988 issue ofScientific American offers a good overview of HIV and AIDS.

Once contracted, herpes and HIV are incurable, since the viruses inserttheir DNA into the chromosomes of infected cells. The fact that theseviruses are incurable highlights the need for methods to reduce therates and incidence of infection among people who are not yet infected.The subject invention is directed solely toward that goal. Thisinvention is not a treatment for people who are already infected withherpes, HIV, or any other sexually transmitted virus; instead, it is amethod of reducing the risk of infection among people who are notinfected, but who may be exposed to sexually transmissible virusesthrough intercourse with potentially infected sexual partners. Briefly,this invention involves topical lubricants that are spread on thesurfaces of the genitals before and during sexual intercourse, whichcontain a selected zinc salt as an anti-viral agent. The lubricant mustbe non-irritating, physiologically acceptable, and free of any adverselong-term effects when used frequently over a prolonged period of time.Preferred zinc salts include relatively low molecular weight organicsalts which have high solubility in water, and which have low pK values(which indicates high levels of ionic dissociation to release freedivalent zinc ions, Zn⁺⁺). Such salts include zinc acetate and zincpropionate. Other organic salts that have somewhat lower levels ofsolubility or dissociation, but which can be used if desired, includezinc butyrate, formate, gluconate, glycerate, glycolate, and lactate.All of these organic salts which have been tested to date have notcaused any irritation in skin, genital, or intercourse tests. Bycontrast, zinc sulfate (which has been used in the past by numerousother researchers trying to find effective ways to treat herpesinfections) causes significant levels of irritation in most people, andis not preferred. Although substantial irritation will be tolerated bypeople who are already infected by genital herpes and who are sufferingan outbreak of lesions, such levels of irritation are not acceptable ina genital lubricant intended for use during sexual intercourse.

Prior Studies on Zinc Salts To Treat Genital Herpes

Prior to this invention, numerous researchers reported that zinc couldinhibit herpes viruses. Some of these test reports involved in vitrocell culture tests (e.g., Gordon et al 1975, Shlomai et al 1975, Guptaand Rapp 1976, Fridlender et al 1978, and U.S. Pat. No. 4,407,818 byLionelle et al). Other test reports involved people or lab animals thathad already become infected with herpes viruses (e.g., DeRoeth et al1963, Jones 1979, Tennican et al 1979 and 1980, Fahim et al 1980a and1980b, Wahba et al 1980, Brody et al 1981, Eby and Halcomb 1985, andU.S. Pat. Nos. 4,465,666 and 4,762,715 (Lukas et al)).

Most of that work was done before the advent of nucleoside analogs suchas acyclovir and gancyclovir. Interest in zinc as a topicalanti-herpetic treatment dropped off sharply after the "high-tech" drugssuch as acyclovir offered more effective treatments.

It should also be noted that several of the articles cited above reportthat zinc salts, by themselves, are not effective in inhibiting herpesviruses unless they are combined with some other agent or treatment thatincreases the effectiveness of the mixture. For example, the reports byFahim et al involve ultrasound treatment of areas treated by ointmentscontaining 30% urea, 3% zinc sulfate, and 2% tannic acid. Obviously,ultrasound treatment of the site of transmission during sexualintercourse is not feasible.

Similarly, U.S. Pat. No. 4,465,666 (Lukas et al) stated that zinc saltsby themselves were not adequately active against herpes viruses. Inorder to render the zinc salts effective for treating herpes, Lukas '666stated that a sulfated polysaccharide such as heparin or dextran sulfatehad to be added to the mixture. However, it would be inadvisable to addheparin or dextran sulfate to a genital lubricant, since repeated use ofeither agent in a genital lubricant could generate severe adverseeffects. Heparin is a powerful anti-coagulant, and it inhibits thegrowth of epithelial cells, which are the type of cells that line themucous membranes inside the vagina and urethra (Wright et al 1985 and1987). Both of these traits indicate that heparin is likely to interferewith the closure and healing of any lesions, cuts, and microabrasions inthe mucous membranes or other genital surfaces. Heparin administrationhas also been associated with skin necrosis (White et al 1979), andheparin apparently is able to penetrate the skin and enter thebloodstream (Aliabeva et al 1980). All of these factors indicate thatheparin would generate various risks of adverse effects in substantialportion of the general population.

Dextran sulfate appears to be even more dangerous. It causes severeulcerations and inflammation in the colon which can lead to coloncancer; this effect is so strong that dextran sulfate is used as thecausative agent in a standard laboratory technique which inducesulcerative colitis and colon cancer in lab animals (e.g., Cooper et al1993 and Yamada et al 1992). It also interferes with fibroblast growth,various types of fluid and cell movement and permeation, and othernatural processes involving the skin (see Sorimachi et al 1992, VanOsselaer et al 1993, and Powis et al 1992). In addition, dextran sulfateis also an anti-coagulant. Although less powerful than heparin, it canalso interfere with the healing and closure of lesions or small cuts orabrasions in the skin or mucous membranes of the genitals.

These adverse effects are regrettable, since both heparin and dextransulfate have been shown to have substantial activity in cell culturetests against HIV, the virus that causes AIDS. However, these risks andadverse effects cannot be ignored, and they apparently render heparinand dextran sulfate dangerous and unsuitable for use in genitallubricants. It should be noted that U.S. Pat. No. 4,869,270 (Ueno et al1989), which claimed the use of dextran sulfate in a condom lubricant,made no mention of the problem of ulcerative colitis caused by dextransulfate, or any of the other physiological problems and dangers listedabove.

It should also be noted that most of the above-cited reports involvingherpes viruses used zinc sulfate, which causes genital irritation and istherefore not well suited to use as a lubricant during intercourse.

Studies on Zinc Which Failed to Show Inhibition of HIV

A number of researchers have performed screening studies on various zinccompounds, to determine whether such compounds might be able to inhibitHIV, the virus that causes AIDS. However, none of the published studiesthat used standardized assays showed any effectiveness for zinc as ananti-HIV agent. Very little has been published in scientific or medicaljournals regarding such tests, since the results were poor; however, thelack of success using zinc against HIV can be documented using items ofpersonal correspondence.

For example, when the Applicant submitted samples of several zinc salts(including zinc acetate and zinc gluconate) to the National CancerInstitute for evaluation in a standardized screening test used toevaluate drugs against HIV (described in Weislow et al 1989), thescientists in charge of the NCI's screening program returned the zincsalts without even opening them. The NCI's letter of response addressedto the Applicant, dated Aug. 8, 1991, stated as follows: "After carefulconsideration, we have decided not to test your zinc salts in ourAIDS-antiviral assay . . . We have tested 36 zinc-containing compoundsin our in vitro AIDS screen, including zinc gluconate. Test results ofthis inactive compound, NSC 619899, are enclosed . . . None of thesematerials has demonstrated any activity worth pursuing . . . Based onthese results, we don't believe that your compounds will show activityin our assay."

This is an authoritative statement by researchers skilled in the art ofHIV research who had tested zinc against HIV, and who did not believethat zinc salts could serve as effective agents against HIV infection.

The Applicant also has been informed by an official of ContraceptiveResearch and Development (CONRAD, a not-for-profit foundation based inAlexandria, Va.) that several zinc salts were tested using an assaydescribed in Resnick et al 1990. According to the CONRAD official, theresults of those tests did not show any substantial anti-HIV activityfor any zinc compounds.

Other Prior Art

Another line of prior art also deserves mention, even though it does notinvolve anti-viral research. In the late 1970's, several zinc salts werestudied to determine whether they might be effective as contraceptivesto avoid pregnancy (Williams 1980, Chvapil 1978, and Chvapil 1980).Williams 1980 tested several formulations, including zinc acetate mixedwith K-Y Lubricating Jelly (a trademark for an aqueous gel sold byJohnson & Johnson, New Brunswick, N.J.). The zinc salts tested byWilliams and Chvapil were only about 80% effective on a single-eventbasis. This is not nearly good enough for practical and effective use asa contraceptive; to be effective as a contraceptive at a 95% or higherlevel over the span of a year or more (where a failure in any single actof intercourse, out of numerous acts of intercourse during the year,results in pregnancy), a contraceptive must be effective at well overthe 99% level during each act of intercourse. Since the results reportedby Williams and Chvapil showed that zinc salts did not have adequatecontraceptive activity, interest in this line of research died out, anda gel containing a zinc salt apparently was never packaged anddistributed for sale or further testing for contraceptive use.

Accordingly, there remains a need for a non-irritating, non-toxicgenital lubricant for use during sexual intercourse, to reduce the riskof viral infection in someone who is not previously infected. Any suchlubricant must be safe and harmless enough for frequent and repeated use(such as daily use) over a period of months or years (obviously, termssuch as repeated or daily use do not imply that the same quantity oflubricant will be used repeatedly; instead, a new quantity of thelubricant will be used during each act of intercourse). The lubricantgel must also be free of any component which is an anti-coagulant (suchas heparin or dextran sulfate) or which could pose a risk of adverseeffects due to frequent and repeated use over a span of months or years.

"Label Claims"

Various unlabelled articles of manufacture, which contain zinc salts invarious types of packages that render the articles useful as anti-viralgenital lubricants, are claimed in U.S. Pat. No. 5,208,031 and invarious pending applications, including Ser. No. 08/057,001 and Ser. No.08/361,967.

By contrast, the claims herein are focused upon and limited to certainarticles of manufacture, which include the zinc-containing lubricantsdescribed herein and the packaging material as tangible, non-printed,non-copyrightable items, and which also contain printed labellinginformation as an additional component of the non-copyrightable packagedlubricant, which increases the utility and anti-viral efficacy of thelubricant.

This patent application, which contains a technical description, is notthe proper forum for a comprehensive legal analysis of the patentabilityof a non-copyrightable item which contains printed information as onecomponent of the item. Briefly, the relevant court precedents includeApplication of Miller, 164 U.S.P.Q. 46 (Court of Customs and PatentAppeals, 1969), which states, "printed matter, in an article ofmanufacture claim, can be given patentable weight . . . no attempt ishere being made to patent printed matter as such. The fact that printedmatter by itself is not patentable subject matter, becausenon-statutory, is no reason for ignoring it when the claim is directedto a combination . . . The solicitor seems to urge that we ignore theclaim limitations to the legends because they are printed and becauseprinted matter is not patentable subject matter by itself . . . wereject that argument" and In re Gulack, 217 U.S.P.Q. 401 (Court ofAppeals for the Federal Circuit, 1983), which declared, "the boardcannot dissect a claim, excise the printed matter from it, and declarethe remaining portion of the mutilated claim claim to be unpatentable .. . A printed matter rejection is based on case law antedating the 1952patent act . . . The 1952 act legislatively revised that approachthrough its requirement that the claim be viewed as a whole . . . "

Additional discussion (which points out, for example, the high costs andheavy burdens of trying to prove "contributory infringement" of a newmethod-of-use claim for an old known drug) is contained in an articlewritten by the applicant and attorney herein. That article was publishedas, "Old Drug, New Use: Article of Manufacture Claims," BIO/TECHNOLOGY11: 839-840 (1993).

It should also be noted (and emphasized) that the Food and DrugAdministration, which together with the U.S. Patent and Trademark Officeshares the primary federal responsibility for encouraging privateenterprise to fund, create, and commercialize improvements inpharmaceutical and medical technology, absolutely requires that anyapplicant seeking approval to market a new drug or device must includerelevant labelling information. Accordingly, since the FDA absolutelyrequires labelling information as an essential part of any item itreviews, then under appropriate circumstances, it becomes entirelyappropriate to regard a packaged drug and its label, taken together, asa single, tangible, non-copyrightable item of commerce which is anappropriate subject for federal scrutiny and review.

Accordingly, one object of this invention is to disclose an article ofmanufacture comprising a genital lubricant gel containing a selectednon-irritating, water-soluble zinc salt at an anti-viral concentration,enclosed within a plastic-walled tubular package which renders the gelconvenient and easy to use during intercourse and which containslabelling information indicating that the lubricant should be spreadupon genital surfaces during sexual intercourse. Such labellinginformation, by recommending use of the lubricant during intercourse,overcomes and avoids all prior art relating to the use of zinc salts totreat outbreaks of herpes lesions in people who are already infected bygenital herpes, since anyone suffering from such an outbreak of herpeslesions is advised to abstain from intercourse until after the outbreakhas subsided and disappeared.

Another object of this invention is to disclose an article ofmanufacture comprising a genital lubricant gel containing a selectednon-irritating, water-soluble zinc salt at an anti-viral concentration,enclosed within a plastic-walled tubular package, wherein the packagecontains labelling information indicating that the gel therein iseffective as an anti-viral agent against at least one type of sexuallytransmitted virus (such as genital herpes viruses, humanimmunodeficiency viruses, hepatitis viruses, or papilloma viruses).

A third object of this invention is to disclose an article ofmanufacture comprising a condom and an aqueous lubricating fluidenclosed within a sealed package, wherein the lubricating fluid containsa selected non-irritating, water-soluble zinc salt at an anti-viralconcentration, and wherein the sealed package contains labellinginformation indicating that the condom lubricating fluid therein iseffective as an anti-viral agent against at least one type of sexuallytransmitted virus (such as genital herpes viruses, humanimmunodeficiency viruses, hepatitis viruses, or papilloma viruses).

SUMMARY OF THE INVENTION

This invention relates to an article of manufacture comprising a genitallubricant containing a selected non-irritating, water-soluble zinc saltat an anti-viral concentration, within a package which containslabelling information indicating that the lubricant is effective as ananti-viral agent against at least one type of sexually transmitted virus(such as genital herpes viruses, human immunodeficiency viruses,hepatitis viruses, or papilloma viruses). One such lubricant comprises alubricant gel enclosed within a plastic-walled tubular package, for usewith or without a condom; another such lubricant comprises a condomlubricant, coated on a condom and sealed along with the condom inside adisposable plastic pouch.

The zinc salt must be water-soluble and have substantial dissociationrates to release divalent zinc ions. Suitable organic salts include zincacetate, zinc propionate, zinc butyrate, zinc formate, zinc gluconate,zinc glycerate, zinc glycolate, and zinc lactate. A gel must alsocontain a thickening agent (such as chemically-treated cellulose) and alubricating agent (such as glycerin), and it must be free of heparin,dextran sulfate, or any other anti-coagulant or other component whichposes a substantial risk of adverse effects if the lubricant is usedfrequently and repeatedly over a period of months or years. Thezinc-containing lubricants described herein can reduce the risk that apreviously uninfected person will become infected by sexuallytransmitted viruses, and the labelling information will help promoteefficacy and slow the spread of incurable viruses.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that HIV infectivity was completely eliminated whenconcentrated viral stocks were incubated with 1% zinc acetate for 2hours before the zinc-virus solution was diluted (1:30) and mixed withsusceptible lymphocytes.

FIG. 2 shows that HIV infectivity was reduced and delayed whenconcentrated viral stocks were incubated with 1% zinc acetate for 2hours before the zinc-virus solution was diluted (1:100) and mixed withlymphocytes.

FIG. 3 shows that HIV infectivity was completely eliminated when variousdilutions of high-titer viral stocks were incubated with 1.5% zincacetate for 2 hours.

FIG. 4 shows that HIV infectivity was either eliminated or suppressedwhen high-titer viral stocks were incubated with various concentrationsof zinc acetate.

FIG. 5 depicts a tube which contains a zinc-containing gel, packagedinside a lightweight box for shipping and display. The box and tube aremarked with labels indicating that the gel should be applied to genitalsurfaces prior to intercourse, and that such use of the gel can reducethe risk of infection by sexually-transmitted viruses.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the use of certain types of non-irritatingwater-soluble zinc salts (such as zinc acetate) that are useful asanti-viral agents, in aqueous lubricants that are packaged in ways thatfacilitate and promote convenient and consistent use as genitallubricants during sexual intercourse. Such anti-viral lubricants can beused with or without condoms, by someone who is not infected with asexually transmitted virus (such as genital herpes viruses or HIV) andwho is at risk of infection, to reduce the risk that he or she willbecome infected if his or her sexual partner is infected.

In one preferred embodiment, the lubricant of this invention comprises azinc-containing aqueous gel enclosed within a plastic-walled tubularpackage which is labelled in a manner indicating that the lubricantshould be spread upon genital surfaces during sexual intercourse. Suchlabelling information, by recommending use of the lubricant duringintercourse, overcomes and avoids all prior art (listed above, in theBackground section) relating to the use of zinc sulfate or gluconate totreat outbreaks of herpes lesions in people already infected by genitalherpes, since anyone suffering from such an outbreak of herpes lesionsis advised to abstain from intercourse until after the outbreak hassubsided and disappeared.

In an alternate preferred embodiment, the lubricant of this inventioncomprises a zinc-containing gel in a plastic-walled tubular packagelabelled in a manner indicating that the lubricant is effective, as ananti-viral agent, against at least one type of sexually transmittedvirus (such as genital herpes viruses, human immunodeficiency viruses,hepatitis viruses, and/or papilloma viruses).

In another alternate preferred embodiment, the lubricant of thisinvention comprises a zinc-containing condom lubricant on the surface ofa condom, wherein both the condom and the lubricant are enclosed withina sealed package (such as a conventional disposable plastic pouch whichcontains a single condom), and wherein the sealed package containslabelling information indicating that the condom lubricant therein iseffective as an anti-viral agent against at least one type of sexuallytransmitted virus.

If a gel is used, a small quantity (such as a teaspoon or severalmilliliters) of the gel is removed from the plastic container and spreadacross one or more genital surfaces, such as the surface of the penisimmediately prior to intercourse, or the accessible surfaces inside thevagina shortly before intercourse, in a manner which causes thelubricant gel to coat and remain in contact with the genital surfaceduring intercourse.

If a lubricated condom is used, the condom is emplaced on or in thegenitals in a conventional manner, depending on the type of condom used.The lubricants of this invention can be used with either conventionalmales condoms, or with so-called "female condoms." They can also be used(preferably in gel form) with diaphragms, cervical caps, or otherbarrier devices; however, such devices are not referred to herein ascondoms.

As used herein, the terms "genital lubricant" and "topical use" refer tosomething that is applied to and spread across the surface of the skinor a mucous membrane. A condom lubricant or other genital lubricant usedas described herein is a topical agent, even though it enters the cavityor vault of the vagina, since it remains within the cavity and does notpermeate through the mucous membrane and enter the bloodstream of thewoman in significant quantities. "Topical" use as defined herein iscontrasted with "systemic" administration, which refers to drugs thatare ingested orally or injected beneath the skin, or to drugs that areformulated in carriers (such as dimethyl sulfoxide) that are used andintended to penetrate through the outermost layers of cells and enterthe bloodstream.

Although the efficacy and practical use of this invention do not dependon a specific molecular mechanism, it is believed by the Applicant thatthe mechanism by which zinc inactivates herpes viruses and HIV is likelyto involve the formation of crosslinking bonds. Positively chargeddivalent zinc ions (Zn⁺⁺) bind to negatively charged unshared electronpairs on the residues of certain types of amino acids (mainly cysteineand histidine) in proteins. This type of crosslinking reaction is wellknown, and is extremely important to certain types of enzymes; inparticular, it creates and stabilizes the "finger domains" in so-called"zinc finger proteins," which carry out crucial interactions withchromosomal DNA.

In the topical lubricant formulations described herein, a similar typeof protein crosslinking reaction apparently allows zinc ions to reactwith proteins on the surfaces of mammalian viruses. This is believed tocause virus particles to agglomerate and bind randomly to each other,and to the surfaces of various cells that cannot be actively infected,including epidermal and epithelial cells that have reached a skin andmucous membrane surfaces of the penis and vagina and which have becomesquamous or pyknotic and are no longer metabolically active in a mannerthat can support viral replication. These more-or-less random bindingreactions reduce the ability of the crosslinked viruses to contact andinfect cells that are susceptible to viral entry or capable ofsupporting viral replication.

This crosslinking reaction has not been reported in any of thescientific articles that describe the use of zinc salts to inhibitviruses. The prior art has reported numerous putative mechanisms whichappear to contribute to the antiviral activity of zinc salts, includinginterference with post-translational processing of capsid polypeptidesin rhinoviruses (Korant and Butterworth 1976), inhibition of DNApolymerase in herpes viruses (Shlomai et al 1975; Fridlender et al1978), interference with herpes protein synthesis (Gupta and Rapp 1976),inhibition of thymidine kinase accumulation and a possible alteration ofRNA synthesis in vaccinia viruses (Zaslavsky 1979), and interferencewith procapsid synthesis in foot-and-mouth disease viruses (Firpo andPalma 1979). All of these reported mechanisms appear to be consistentwith the ability of zinc to form crosslinking bonds with proteins, andthe crosslinking mechanism suggested herein may offer a unifyingexplanation for the numerous other molecular mechanisms that have beenreported in the prior art.

Absence of Irritation by Zinc Acetate in a Gel Carrier

One of the crucial discoveries that led to the subject invention was thediscovery, by the Applicant, that certain types of zinc salts can beincluded at substantial concentrations in gels which can be used asgenital lubricants during a complete act of intercourse, without causingany noticeable irritation to either the male or female. This discoverywas significant and unexpected, for three reasons.

First, much of the prior research which used zinc salts against herpesviruses used zinc sulfate, which causes substantial burning andirritation in most people, especially on mucous membranes. Burning andirritation can be tolerated in a treatment for herpes lesions, if thetreatment will make the lesions heal more rapidly in someone who isalready infected. However, significant burning and irritation will notbe tolerated by most people in genital lubricants intended for useduring intercourse. Accordingly, zinc sulfate is not included within therange of zinc salts that are suitable for use as described herein. Ifdesired, a small amount of zinc sulfate could be included in a lubricantas described herein, but at least one other genuinely non-irritatingzinc salt would also need to be included in the lubricant in order forthe lubricant to fall within the covereg of the claims below.

Second, the absence of any irritation by salts such as zinc acetate andzinc propionate when dissolved in a gel carrier is somewhat surprising,since zinc acetate or zinc propionate do cause a substantial amount ofburning and irritation when dissolved in water alone. This unexpecteddisappearance of any irritation when zinc acetate is dissolved in a gelcarrier, rather than water, is described in more detail below.

And third, zinc salts are well known to be astringents (agents thatcause a drying effect, blood vessel constriction, and/or tissuecontraction). The Merck Index (11th edition, 1989) explicitly listsnearly all the zinc salts that are of widespread pharmaceutical interest(including zinc acetate, zinc carbonate, zinc chloride, zinc iodide,zinc salicylate, zinc stearate, zinc sulfate, and zinc tannate) asastringents. Astringents are well-suited for treating outbreaks ofherpes lesions, since one of the main goals of treating herpes lesionsis to dry out the virus-laden fluids that fill the blisters and lesions.However, an astringent is the opposite of what people normally want in alubricant, especially a lubricant applied to the genitals duringintercourse. People do not want drying, vasoconstricting, or otherastringent activities occurring on their genitals during sexualintercourse. Therefore, the fact that zinc salts are astringents teachesdirectly and strongly away from their use in genital lubricants intendedfor use during intercourse. However, in this invention, the use by theApplicant of a suitable lubricant gel carrier substance made primarilyof water, and which contained thickening and lubricating agents inaddition to the water, overcame the astringent effects of zinc. Nounpleasant or noticeably astringent effects were observed by the humanvolunteers who tested gels with zinc acetate or zinc propionate in gelsduring intercourse.

Suitable Zinc Salts

As mentioned above, the anti-viral activity of a zinc salt in an aqueouscarrier is presumed to be due to the action of zinc ions that have beenreleased by the salt. Three factors are important in determining theconcentration of zinc ions that will be present in an aqueous carrierfluid if a certain zinc salt is dissolved in the fluid. Those factorsare:

(1) The solubility of the zinc salt in water. This value is oftenexpressed in terms of grams of salt per 100 cubic centimeters (0.1liter) of saturated solution. That figure can be converted into agrams/liter basis by multiplying it by 10.

(2) The molecular weight of the salt, which allows a weightconcentration to be converted into a molar concentration. For example,the molecular weight of zinc acetate is 183.4, so 183.4 grams of zincacetate is equal to one mole (=6.02×10²³ molecules). Molarconcentrations are usually expressed in molar (M) units, which refer tomoles of a compound per liter of solution, or in millimolar (mM)concentrations, which refer to thousandths of a mole per liter.

(3) The rate at which the salt dissociates into cations and anions. Thisis usually expressed on a base 10 logarithmic scale using pK values,which are often called equilibrium constants, stability constants, ordissociation constants. Like pH values for acids, if the pK value of asalt is low, the rate of ionic dissociation for that particular salt ishigh. Solubility and pK values for several zinc salts are provided invarious published reports, such as Sillen and Martell 1964 and 1971,Lide 1990, Linke 1965, and Cannan and Kibrick 1938.

Since zinc gluconate has already been reported to be effective incombatting established herpes infections (Eby and Halcomb 1985), zincgluconate can be regarded as a benchmark of effectiveness. Other zincsalts that are comparably soluble (or preferably more soluble) and whichhave comparable (or preferably lower) pK values, when compared to zincgluconate, can be presumed to be effective in inhibiting herpes virus.

Two zinc salts which are especially preferred for use as describedherein, because they have high solubility in water and high ionicdissociation rates (low pK values), are zinc acetate and zincpropionate. Various other zinc salts that also offer good candidates forevaluation (based on published solubility and pK values, include zincbutyrate, zinc formate, zinc gluconate, zinc glycerate, zinc glycolate,and zinc lactate. The anti-viral effectiveness of any of these salts (orany other candidate salt) in an aqueous gel or condom lubricantformulation can be tested using in vitro tissue culture tests or in vivoanimal tests, as described in above-cited U.S. Pat. No. 5,208,031.

Among other things, this invention is based on the discovery thatcertain zinc salts that are soluble in water do not irritate the skin ormucosal membranes of the penis or vagina, even when a lubricantcontaining such a salt is rubbed into the skin or membrane over asustained period of time, as occurs during intercourse. Zinc acetate andzinc propionate were both tested for irritation; although each of themcaused vaginal irritation when dissolved in water alone, they were foundto be non-irritating when mixed with K-Y Lubricating Jelly atconcentrations up to about 5% weight/volume and used as a lubricantduring a complete act of heterosexual intercourse.

Zinc butyrate also has a high rate of ionic dissociation; since it isless soluble than zinc acetate or propionate, it was not tested forirritation.

Zinc gluconate was also tested and did not cause any irritation duringintercourse. However, it does not have a high degree of solubility inwater, and when extensively ground in a mortar and pestle and then mixedthoroughly in a gel, the gel contained very fine, small particles whichdisplayed a very slight roughness when rubbed hard between theforefinger and thumb. Although no abrasion or irritation was noticeableby either person during intercourse, it is not recommended for use in alubricant, due to the risk of creating microabrasions that might helpviral particles penetrate skin or mucous membranes.

Other organic salts that appear to be less preferred, since they areless soluble in aqueous solution and/or because they have relativelyhigh pK values, include zinc salicylate, zinc citrate, zinc oleate, zincbenzoate, zinc laurate, and zinc tartrate. Several other organic saltsof zinc were obtained and evaluated, including zinc stearate, zincsalicylate, and zinc valerate. None of those salts caused any irritationduring forearm or male genital tests; however, each had other drawbacks.Zinc valerate, although soluble in water, has an unappealingdirty-looking color and an unpleasant odor. Zinc stearate and zincsalicylate have very low solubility in water, and also have unpleasantodors. Accordingly, even though they caused no irritation in forearm ormale genital tests, they were not tested vaginally or duringintercourse.

Although non-polymeric salts with low molecular weights are preferred,it may be possible to use a zinc salt formed from a polymeric componentof a gel, such as a cellulose derivative or some other polymer orpolysaccharide used as a thickening or lubricating agent. Several suchpolymeric compounds which might be converted into polymeric zinc saltsfor use herein are described below.

Zinc Salt Concentrations

Rather than trying to determine a single concentration of a zinc saltthat would be optimal for everyone, the effectiveness of this inventioncan be enhanced by selling lubricants having a range of different zincconcentrations, for different people. By way of analogy, since somepeople are easily sunburned while others are highly tolerant of directsunlight, suntan oils and creams are sold with a range of "sunprotection factors." Anyone is free to choose his or her preferredformulation, based on both skin type and anticipated exposure. Asanother example, contraceptive gels containing 1% to 4% nonoxynol, andcondoms lubricated with fluids containing 5 to 15% nonoxynol, are bothsold over-the-counter, and purchasers are free to choose theconcentration they prefer.

In a comparable manner, genital lubricants having a range ofconcentrations of anti-viral zinc salts can be made available, andpeople having varying sensitivities, sexual habits, and levels ofconcern over sexually transmitted viruses, can choose the concentrationsthey prefer. People who are at relatively low risk, or who havesensitive skin or are highly susceptible to psychosomatic suggestions ofirritation, might prefer to use a formulation having a relatively lowconcentration, such as about 0.5% to 3%, expressed as weight per volume,w/v, calculated as grams of zinc salt per milliliter of fluid,multiplied by 100 to convert the ratio to a percentage). People who arehighly sexually active and non-monogamous, or who live in cities withhigh rates of sexually transmitted diseases, might choose to use alubricant containing 30% or more of a zinc salt. This 30% figure mightseem high, but it should be noted that:

(1) It indicates the weight of the salt, rather than the weight ofelemental zinc. A compound containing 30% w/v zinc acetate would containabout 10.7% elemental zinc.

(2) Preparations used for other surface applications are soldover-the-counter which contain more than 30% elemental zinc; and,

(3) Relatively small quantities of lubricant are typically used inconjunction with condoms. For example, while spermicidal gels for usewithout condoms usually contain about 5% or less nonoxynol as aspermicide, condom lubricants contain up to 15% nonoxynol. Accordingly,a condom lubricant or a gel intended for use with a condom may have asomewhat higher concentration of a zinc salt than a gel intended for usewithout a condom.

(4) The lubricant usually becomes diluted by the female's natural fluidsafter intercourse begins.

Accordingly, this invention anticipates lubricants containing zinc saltsin the range of about 0.5% to about 30% w/v.

As used herein, references to "non-irritating" refer to formulationsthat cause no irritation, or acceptably low levels of irritation, in atleast some people. Such formulations can be used by such peopleregardless of whether they might cause irritation in other people whoare more susceptible. In addition, the anti-viral lubricants of thisinvention can be used even though they may cause some irritation in theuser; many people would regard a low level of mild irritation as areasonable and necessary price for an added level of safety, comparableto the loss of sensitivity that accompanies condom use.

Anyone buying such a lubricant gel or condom should be clearly warnedthat the lubricant does not offer completely reliable, 100% protectionagainst herpes infection. Nevertheless, the anti-viral sexual lubricantsof this invention can reduce the risk of becoming infected. Accordingly,in the absence of any effective vaccines or cures for herpes or AIDS,most rational people who are at risk would prefer to take the precautionof using a lubricant which offers nearly any significant increase inprotection, provided the lubricant is genuinely safe, non-toxic, andnon-irritating.

Aqueous Gels (Carrier Fluids)

In addition to an anti-virally effective zinc salt, a gel for use asdescribed herein should have the following components, which arediscussed in more detail in the above-cited U.S. Pat. No. 5,208,031:

a. water;

b. a thickening agent such as cellulose or a chemically treatedderivative of cellulose, acacia, agar, alginate, carrageenan, gumtragacanth, xanthan gum, collagen, carboxypolymethylene, glycerylmonostearate, polyvinylpyrrolidone, and polyacrylamide; and,

c. a lubricating agent such as glycerin, propylene glycol, polyethyleneglycol, polypropylene glycol, polyisobutene, polyoxyethylene, behenicacid, behenyl alcohol, sorbitol, and polydimethylsiloxane.

The thickening and lubricating agents listed above are not biologicallyactive, and basically serve as carrier substances.

As used herein, "lubricating agent" refers to a component which isincorporated into a genital lubricant for the purpose of reducingfriction during intercourse. Although any liquid (including water) cansometimes function as a "lubricant" in the broadest sense of the word,four characteristics distinguish a "lubricating agent," as that term isused herein, from water and other liquids that do not have thecharacteristics necessary for effective and comfortable lubricationduring sexual intercourse: (1) a proper lubricating agent issubstantially more viscous than water and feels slippery when rubbedbetween two skin surfaces; (2) a lubricating agent should have anaffinity for human skin, and when applied to skin, it should spreadsmoothly and evenly across the contacted area; (3) a lubricating agentshould remain in contact with the skin, clinging to it in a moresubstantial manner than water, which is easily wiped away; and, (4) alubricating agent should have a low level of volatility, and should notevaporate quickly. The foregoing characteristics can be easilyrecognized and understood on a practical level by rubbing a conventionallubricating agent (such as glycerin or mineral oil) between the fingers.The nature and the durability of the lubrication, and the differencesbetween such agents and less suitable liquids such as water, are readilyapparent.

In addition, in order to be physiologically acceptable, a selectedlubricating agent should not cause any significant adverse effects (suchas irritation, tenderness, swelling, redness, or skin discoloration),and must not pose a significant risk as a carcinogen or teratogen.Further, in contrast to non-physiological lubricants such as motor oil,physiologically acceptable lubricating agents should be either graduallybroken down into innocuous substances in the body if they are absorbedby tissue to a significant degree through the skin or mucous membranes,or they should be of a nature that allows them to be secreted by thevagina and washed cleanly from the skin, so that they will not foul andclog the pores in membranes or dermal layers.

Several lubricating agents which are used in commercially availablesexual lubricants satisfy these criteria, including glycerin (alsocalled glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane)and certain types of polyethylene glycol (PEG), such as PEG 200 or PEG400 (the numbers indicate different molecular weight averages). Variousother polymers (such as polypropylene glycol, polyisobutene, andpolyoxyethylene) and behenic acid and behenyl alcohol are also used aslubricants in cosmetics and other formulations that contact the skin. Inaddition, some sugar-alcohols such as sorbitol, and some siliconcompounds such as polydimethylsiloxane, are also used as skin-contactinglubricating agents.

Because glycerin, propylene glycol, polyethylene glycol, andpolypropylene glycol have long been used in sexual lubricants and otherskin-contacting formulations with no adverse effects, they are preferredfor use as lubricating agents in the anti-viral sexual lubricants ofthis invention. The suitability of any other candidate lubricating agentas a condom lubricant as described herein can be determined throughroutine experimentation in humans to ensure that it will not causeirritation or other adverse effects, and in in vitro cell culture and invivo lab animal tests (as described in U.S. Pat. No. 5,208,031) toensure that the candidate lubricating agent does not substantiallyreduce the anti-viral effectiveness of a lubricant gel containing a zincsalt.

A suitable thickening agent which is widely used in genital lubricantscomprises chemically treated derivatives of cellulose (such ashydroxyethyl- or hydroxymethyl-cellulose). Other thickening agents whichhave been used in skin-contacting compounds, and which offer candidateagents for potential use in zinc-containing genital lubricants, includeacacia, agar, alginate, carrageenan, gum tragacanth, xanthan gum,collagen, carboxypolymethylene, glyceryl monostearate,polyvinylpyrrolidone, and polyacrylamide.

Other components, including preservatives (such as chlorhexidinegluconate), anti-crystallization agents (such as glucono-delta-lactate),fragrances, coloring agents, alkaline or acidic or buffering agents tomaintain the proper pH, and soothing or anti-swelling agents (such aslanolin, aloe vera extract, or hydrocortisone) can be added to thecondom lubricants described herein. However, at the concentrations used,any such additive should not seriously impede the anti-viral activity ofthe zinc salt due to reactions such as chelation, and should notirritate or have other adverse effects on the genitals.

The complete gel mixture must be physiologically safe and acceptablewhen used repeatedly, during numerous acts of intercourse over a periodof months or years, and it must not irritate mucous membranes or othergenital surfaces even when rubbed in vigorously, as often occurs duringintercourse. The gel must also be free of anti-coagulants (particularlyheparin or dextran sulfate) or other components which could pose a riskof adverse effects in a significant portion of the population.

A deformable-walled plastic tube for use as describd herein can be aconventional plastic tube, as used for toothpaste and numerous othercosmetic and hygiene products. Such tubes usually are permanently sealedat one end (such as by heat-crimping), and have a removable cap coveringan outlet orifice at the other end. The cap can be a threaded screw-oncap, or a hinged flip-type cap which can be opened without detaching itfrom the tube so that it cannot be lost and can be opened or closedeasily with one hand. Between the two ends of the tube, the containerhas at least one deformable plastic wall, which preferably should beessentially tubular, comparable to a toothpaste tube, with atransitional shoulder or neck region leading to the outlet orifice.

The gel is removed by the simple act of opening the cap, squeezing out adesired quantity of gel (such as a teaspoon or several milliliters), andclosing the cap again, just like a standard tube of toothpaste.

In one preferred embodiment, the deformable plastic wall(s) can be thinand pliable enough so that they will tend to retain the new shape thatis created when a quantity of gel is squeezed out of the tube, in amanner comparable to walls made of deformable metallic foil. Yieldingdeformation will help protect the gel remaining in the tube, against airand oxygen. By contrast, if the walls of the tube are resilient and tendto return to their initial shape, they will tend to draw air into thetube as soon as the squeezing pressure is released. Any air that entersthe tube before the cap is replaced can promote oxidative degradation ofthe gel remaining in the tube.

Sufficiently thin plastic walls can also offer an additional benefitwhich involves warming up the lubricant gel prior to intercourse. Thiscan be done by placing the tube, preferably with the cap securelyfastened and pointing down, in a cup or glass of warm or hot water, suchas on a table or nightstand next to a bed. The walls of the tube conveyheat from the warm water into the gel, to warm up the lubricant gel to apleasant and comfortable temperature, close to 37° C. (98.6° F.) orslightly warmer, before the gel is spread upon the surfaces of thegenitals. Although this might seem like a trivial gesture to some, thisprocedure allows the use of such a lubricant to be turned into a form ofpleasant foreplay which can encourage consistent and reliable use ratherthan sporadic and inconsistent use. In the age of AIDS, even a singleact of neglect can lead to catastrophic illness and a horrible,lingering death. Therefore, any factor that can promote and increaseconsistent, steady, and reliable use of an anti-viral agent duringnumerous acts of intercourse over a span of months or years can be ofenormous benefit, and can literally make the difference between life anddeath.

It should be recognized that Williams 1980 reported laboratory tests onzinc acetate mixed with K-Y Lubricating Jelly as a potentialcontraceptive. However, the data from Williams' tests (and similar testsreported in Chvapil 1978 and Chvapil 1980) showed zinc acetate and otherzinc salts to be only about 80% effective as a contraceptive, on asingle-event basis. As noted in the Background section, that level ofefficacy was not nearly good enough for effective long-term use as acontraceptive, and a gel containing both a zinc salt and a lubricatingagent was never packaged or distributed for sale or further testing.Accordingly, the unlabelled gel-tube article of manufacture disclosedherein has never before been created, and it offers an important newutility. The additional provision of labelling information on the tubewill carry the claims article of manufacture even further away from theprior art.

Apparent Ability of Zinc to Inhibit HIV

In addition to reducing the risk of infection by herpes viruses, zincsalts used in genital lubricants may also be able to reduce the risk ofinfection by the human immunodeficiency virus (HIV). Examples 8-10,below, provide data indicating that in a two-step incubation assayinvolving a first incubation of zinc acetate with HIV viruses, beforesusceptible lymphocyte cells are added for the second incubation step,the zinc inhibited or entirely inactivated the HIV particles.

This two-step incubation assay grew out of the realization by theApplicant that, while zinc is toxic to lymphocytes (white blood cells)at the concentrations of interest, such concentrations will never bereached or even approached in the bloodstream, regardless of theconcentration of zinc in a topical genital lubricant. As described inVallee and Falchuk 1993, a review article which discusses the numerousphysiological roles of zinc inside the body, the concentrations of zincin the bloodstream and other bodily fluids are very tightly regulated,since zinc is a crucial cofactor for literally hundreds of enzymes andproteins. If zinc concentration in the blood starts to rise above normallevels, the body responds by using zinc-binding proteins in the blood tobind to the free zinc, thereby sequestering it in inactive form, and byinducing various secretions in the kidneys and pancreas which causeexcess zinc to be excreted in the urine and feces.

In view of these factors, it became clear to the Applicant that thestandard screening assays used by the National Cancer Institute andothers (such as the assays described in Weislow et al 1989) cannotprovide an adequate screening test to evaluate potential anti-viralagents that might be safe and effective in topical genital lubricants.The standard assays involve mixing together HIV particles, a candidateanti-viral drug, and susceptible lymphocytes, and culturing all threecomponents together in a single long incubation period. Those assayscannot model or simulate what happens inside a vagina during and afterintercourse, where an anti-viral drug might be able to inactivate HIVparticles before the viruses can penetrate through the skin, enter thebloodstream, and contact susceptible lymphocytes. If an anti-viral drugin a topical lubricant can inactivate HIV particles inside the vagina,before the HIV particles can reach the bloodstream, and if the drug willnot penetrate the mucous membranes and enter the blood at dangerouslevels, then the drug might be safe and effective as a topical genitallubricant regardless of how toxic it may be to lymphocytes.

To evaluate this possibility, the Applicant developed and tested atwo-step incubation assay, as mentioned above and as described in moredetail in Examples 8 and 9. The first step of this assay models whathappens inside the vaginal cavity. The candidate anti-viral drug (zincacetate) was mixed and incubated for a relatively brief period (twohours, in the tests used by the Applicant) with HIV particles. Followingthis first incubation step, the zinc/virus mixture was diluted to aconcentration where (1) the zinc would not be toxic to lymphocytes, but(2) the viral particles would still have sufficiently highconcentrations to be highly infective. Susceptible lymphocyte cells werethen added to this mixture, and a second incubation step was carried outfor 20 days or longer, to determine whether zinc-treated or untreatedHIV viruses would infect the lymphocytes.

The results, shown in FIGS. 1-4, clearly indicate that the zincpretreatment step either (1) totally inactivated the HIV viruses, intests involving high-concentration zinc acetate or diluted viruses, or(2) inhibited, suppressed, and delayed the infectivity of the HIVparticles, in other tests involving extraordinarily high concentrationsof HIV that will not occur in nature.

In addition to these data, the Applicant has discovered that it may be avaluable trait for zinc salts in a genital lubricant to be toxic tolymphocytes. It has been reported that epithelial cells (which cover thesurfaces of mucous membranes) can be infected by HIV, even thoughepithelial cells do not have the CD4 receptor proteins that HIVparticles normally bind to. This infection occurs by means of acell-cell binding reaction which bypasses the normal virus-cell bindingmechanism. In the cell-cell binding reaction, HIV-infected lymphocytesin an ejaculate from an HIV-infected male apparently can bind toepithelial cells on the surfaces of mucous membranes. The HIV-infectedlymphocytes then inject HIV particles directly into the epithelial cells(Levy 1988; Phillips and Bourinbaiar 1992; Pearce-Pratt and Phillips1993; Zacharopoulos et al 1992). Therefore, if a genital lubricantcontains a zinc salt at a concentration which is toxic to lymphocytes,then the zinc salt will reduce or eliminate the ability of HIV-infectedlymphocytes in an ejaculate to carry out the cell-cell infectionmechanism. This appears to be a highly useful property ofzinc-containing genital lubricants which is completely independent ofthe direct action of zinc ions in inhibiting free-floating virusparticles.

It should also be noted that semen and ejaculates containextraordinarily high concentrations of zinc. While zinc is present inblood at tightly regulated concentrations of only about 1 μg/ml, zinc ispresent in semen at up to 500 μg/g, and in prostate fluid at up to 1000μg/g (Eliasson and Lindholmer 1971; Fair et al 1976; Homonnai et al1978; Marmar et al 1980). In prostate fluid, zinc exerts anantimicrobial effects, to combat infections that cannot be directlycombatted by the immune system (Fair et al 1976). And in undilutedsemen, zinc suppresses the respiratory activity and motility of spermcells (Eliasson 1971; Paz et al 1977). Apparently, this allows the spermcells to stay in a quiescent state, storing and conserving their energyuntil it is needed. After ejaculation, the zinc is diluted by thefemale's vaginal fluids and by binding to proteins and cell surfacesinside the vagina. This decrease in the concentration of sperm-boundzinc after ejaculation allows the respiratory activity and motility ofthe sperm to increase.

Finally, it should also be noted that there is a very rapid turnover ofepithelial cells on the surfaces of mucous membranes inside the vagina.After an epithelial cell reaches the surface of a membrane inside thevagina, it usually remains there only about four days before it issloughed off and washed out of the vagina by the normal flow of vaginalfluids (Averette et al 1970; Ferenczy et al 1979).

The foregoing physiological factors are important, because they indicatethat the mucous membranes in the vagina are adapted to withstandingconcentrations of zinc that may be hundreds of times higher thanlymphocytes can withstand.

EXAMPLES EXAMPLE 1: GENITAL IRRITATION TESTS USING ZINC ACETATE

In all examples, the test subjects were a monogamous married couple,free of genital herpes or any other sexually transmitted viruses.

Zinc acetate was purchased from Pfaltz and Bauer (Waterbury, Conn.).About 0.5 grams were mixed with several drops of distilled water at roomtemperature. Upon stirring, the salt dissolved completely. The aqueousmixture was rubbed into an area about 3 cm in diameter on the forearm ofthe male and caused no irritation. Subsequently, about 0.5 grams of thesalt were dissolved in a few drops of distilled water, then 10 ml K-YLubricating Jelly (sold by Johnson and Johnson, New Brunswick, N.J.) wasadded to form a gel mixture containing about 5% zinc acetate (w/v). Thiscommercially available mixture contains purified water,hydroxyethyl-cellulose as a thickening agent, glycerin as a lubricant,glucono-delta-lactate to prevent crystallization, chlorhexidinegluconate as a preservative, and sodium hydroxide to reduce the acidity.

The mixture of zinc acetate in K-Y Lubricating Jelly was tested on themale genitals, passively at first and then with active rubbing. Itcaused no irritation in either test.

When 0.5 grams of zinc acetate was dissolved in distilled water andapplied to the shallow region of the vagina by the female volunteer, itcaused an unpleasant tingling or mild burning sensation that subsidedwithin about ten seconds. However, when mixed with K-Y Lubricating Jelly(5% w/v as above) and applied to the shallow region of the vagina in agel mixture, it caused no tingling, burning, or other unpleasantsensation in a passive test.

Subsequently, the gel formulation was applied topically and used as asexual lubricant during intercourse. Both people wiped off the excesswith a tissue after intercourse, but neither person showered or washedoff the lubricant until the following day. It caused no irritation toeither person.

EXAMPLE 2: ZINC PROPIONATE

Zinc propionate was purchased from Pfaltz and Bauer. About 0.5 gramswere dissolved in several drops of distilled water and tested on themale's forearm and genitals. Although no irritation occurred on the skinin either location, the aqueous mixture caused substantial irritation tothe urethra.

About 10 ml of K-Y Lubricating Jelly was added to the aqueous mixture,to create a gel mixture of about 5% w/v, which was tested, passively atfirst and then with active rubbing, on the male's genitals. It did notcause any irritation in either test. Another quantity of a 5% w/v gelmixture was prepared and tested passively in the shallow regions of thefemale's vagina. It caused no irritation, so it was used as a lubricantduring intercourse. Both people wiped off the excess with a tissue afterintercourse, but neither person showered or washed off the lubricantuntil the following day. It caused no irritation to either person.

EXAMPLE 3: ZINC GLUCONATE

Zinc gluconate was purchased from Ruger Chemical Company (Irvington,N.J.). It came in the form of a white granular powder which was grittyand interspersed with hard granules of varying sizes. About 0.5 gramswere ground into a fine powder using a mortar and pestle for severalminutes. The grinding was repeated after several drops of distilledwater were added, and again after 10 ml of K-Y Lubricating Jelly wasadded. The concentration of the zinc gluconate in the gel mixture wasabout 5% w/v.

The mixture of zinc gluconate and K-Y Lubricating Jelly was tested onthe forearm, male genitals, and female genitals. It caused noirritation, so it was applied and used as a lubricant duringintercourse. Although it caused no irritation and no abrasion wasnoticeable by either person during intercourse, the finely groundparticles in the gel displayed a very slight roughness when rubbed hardbetween the forefinger and thumb. Therefore, unless zinc gluconate canbe thoroughly dissolved in a gel by means such as heating or addition ofan additional agent to increase solubility, zinc gluconate is notpreferred, because of the potential for microabrasions by anyundissolved particles that remain suspended in the gel without fullydissolving.

EXAMPLE 4: ZINC STEARATE, SALICYLATE, AND VALERATE

Zinc stearate, zinc salicylate, and zinc valerate were purchased fromPfaltz and Bauer. All three salts were tested for irritation on theforearm and male genitals, and none caused any irritation. However, dueto other drawbacks, they were not tested during intercourse. Zincstearate and zinc salicylate are insoluble in water, even when mixedwith hot water and ground for several minutes using a mortar and pestle.In addition, both have strong unpleasant odors. Zinc valerate, althoughsoluble in water, has an unappealing dirty-looking color and a strongunpleasant odor.

EXAMPLE 5: ZINC SULFATE

Zinc sulfate in crystalline form was purchased from Sigma ChemicalCompany (St. Louis, Mo.). One gram was ground into a fine powder in amortar and pestle, then 15 ml of K-Y Lubricating Jelly was added andthoroughly mixed. The mixture did not cause any irritation to the male'sforearm, genital skin, or urethra, even when rubbed in actively.However, it caused a tingling, burning sensation when applied in apassive test to the female, so it was not tested during intercourse.

EXAMPLE 6: ZINC CHLORIDE

Zinc chloride in crystalline form was purchased from Sigma ChemicalCompany (St. Louis, Mo.). One gram was ground into a fine powder using amortar and pestle, then dissolved in water and applied to the forearm ofthe male. It caused a burning sensation and was not tested further.

EXAMPLE 7: ZINC OXIDE

Zinc oxide, which is not a salt in the normal chemical sense, is knownto cause little or no irritation. For example, an ointment sold underthe trade name "Desitin" (Pfizer, Inc., New York City), which contains40% zinc oxide, is spread on baby bottoms to control diaper rash andother skin irritations. Other zinc oxide ointments are also applied tothe skin for various purposes, such as on the nose to prevent sunburn.One such ointment, sold at Walgreen's (Walgreen Laboratories, Chicago,Ill.), contains 20% zinc oxide in an ointment base of white wax,petrolatum, and mineral oil.

In skin irritation tests using the Walgreen's 20% ointment, tests on theforearm or male genitals were deemed unnecessary. Approximately 5 ml ofthe 20% zinc oxide ointment was mixed with K-Y Lubricating Jelly toreduce the viscosity of the zinc ointment. The mixture was testedpassively by the woman to ensure that it did not cause any irritation,then it was used as a lubricant during intercourse. Other than being abit sticky and viscous, it did not cause any significant irritation toeither person.

While the zinc acetate and propionate gels were clear, zinc oxide is abright, opaque white color. Therefore, it is more likely to generatevisible stains on bedsheets and underwear than water-soluble zinc salts.

EXAMPLE 8: HIGH-TITER HIV INFECTIVITY TESTS

HIV tests were carried out at Biotech Research Laboratories (Rockville,Md.). The HIV-1 viral isolate and H-9 cell line were originally suppliedby Robert Gallo of the NCI.

In a first set of tests, 20 mg of zinc acetate powder (ZnAc, MW 183.4)was mixed in 1 ml RPMI cell culture medium (Whittaker Corp.). This 2%(w/v) salt mixture contained 7 mg/ml elemental Zn. Although ZnAc ishighly soluble in water, it generated a precipitate in the culturemedium, which contains protein. Therefore, a small quantity of HCl wasadded until the mixture became clear; the pH was about 5.5. The Znconcentration was reduced by half (and the pH was raised somewhat) whenan equal volume (1 ml) of cell-free high-titer HIV-1 viral stock wasadded. The zinc/virus mixture was stirred and incubated for 2 hours at37° C.

Following this first incubation step, the zinc/virus mixtures werediluted at 1:10, 1:30, and 1:100 ratios using culture medium, andaliquots were added to equal volumes of culture media containing H-9lymphocytes that had been pretreated overnight with 2 μg/ml Polybreen.The lymphocyte mixtures were incubated for three hours at 37° C.; zincconcentrations during this step were 180, 60, and 18 μg/ml for the 1:10,1:30, and 1:100 dilutions.

The cell aliquots were then washed twice, using culture medium, toremove free p24 proteins that are present in the initial viral stock.Such proteins will skew ELISA readings if not removed by washing. Cellswere then resuspended in fresh medium containing 10% fetal calf serum(FCS) and cultured for 20 days. During this period, each tube wasperiodically sampled by hand-mixing the tube, withdrawing 100 μl ofliquid from the top, and testing the sample for p24 antigens using ELISAassays.

The 1:10 dilutions, which contained 180 μg/ml Zn during the 3-hourincubation prior to washing, caused substantial mortality to thelymphocytes, and resulting ELISA data were discarded.

Based on visual observations, 1:30 dilutions (60 μg/ml Zn) retarded cellgrowth during the first few days; however, any such effect disappearedwithin a few days and the cells grew well during the rest of the assayperiod.

A positive control was used at each dilution. Viral aliquots not treatedwith zinc were identically diluted, mixed with lymphocytes, cultured,and tested. Negative controls were also run, in which H-9 cells wereplated and grown in the absence of any virus or zinc; these providedbackground levels that vary slightly from day to day, depending onfactors such as spectrophotometer calibrations and rinsing conditions.

Optical density (OD) data from the 1:30 dilution test are shown inFIG. 1. These quantities are averages based on triplicate samples. Thep24 concentrations were indistinguishable from background levels, whichindicates that the zinc treatment completely abolished viralinfectivity.

Data from the 1:100 dilution test are shown in FIG. 2. One of the tubesbecame infected by mold after the 10th day, so subsequent values arebased on averages from two samples. These results indicated that thezinc suppressed and retarded HIV infectivity; however, apparently, somesmall fraction of the viruses apparently remained infective.

EXAMPLE 9: DILUTED HIV INFECTIVITY TESTS

The tests described above, in Example 8, used an undiluted high-titerviral stock, which contained at least ten million infectious viralparticles per ml. That concentration can be achieved in a laboratoryonly by special culturing, purification, and concentration techniques,and it is vastly higher than would actually occur in the ejaculate of anHIV-infected person (especially someone who is not in the end stages ofthe disease, and who might pose a significant risk of transmitting thevirus to an uninfected and unknowing sexual partner).

In a subsequent series of tests, ZnAc was tested against diluted viralstocks; in these tests, the zinc completely eliminated the infectivityof the infected viruses. These tests used serial dilutions of the viralstocks, at ranges from 1:10 to 1:10,000. To create the 1:10 dilution,500 μl of viral stock was mixed with 4.5 ml of RPMI medium. Subsequentdilutions added 9 ml of RPMI medium to 1 ml from the preceding dilution.

A 2 ml aliquot from each dilution was mixed with an equal volume of 3%ZnAc dissolved in sterile distilled water; after mixing, the zincconcentration was 5.3 mg/ml Zn. These mixtures were incubated for 2hours, then diluted with culture medium at 1:30, 1:100, and 1:1000 toreduce the toxicity of the zinc to lymphocytes. Four ml of lymphocyteswere mixed with 4 ml of each zinc/virus mixture. The zinc/virus/cellmixtures were incubated at 37° C. for 3 hours; zinc concentrations were88, 27, and 2.7 μg/ml in the 30, 100, and 1000 dilutions. Duringsubsequent culturing, significant cell mortality was observed in the 88μg/ml treatment batch, but no cell mortality was observed at the lowerlevels.

Following the 3 hour incubation, the cells were washed twice in RPMImedium and resuspended in fresh medium containing 10% FCS. Each solutionwas inoculated (2 ml; estimated minimum 2×10⁵ cells per well) into eachof three wells in a 12-well plate and cultured for 27 days, withperiodic sampling and measuring of p24 antigens.

ELISA data for the 10×, 100×, and 1000× high-titer viral stockdilutions, treated with the 1000× dilution of the zinc/virus mixture(2.7 μg/ml Zn final concentration) are shown in FIG. 3. As shown, thezinc treatment completely blocked infectivity. Data for the dilutedviral stocks treated with 1:100 zinc/virus dilutions (27 μg/ml Zn) werevirtually identical, and viral infectivity was completely blocked.

Negative controls were identically diluted cells that did not containzinc or HIV. Positive controls used 1:1000 dilutions of viral stockmixed with zinc-free RPMI. These controls were consistently highlyinfectious, even though their concentrations were 100× lower than the1:10 mixtures in which infectivity was eliminated by zinc treatment.Other positive controls were tested at up to 100,000× dilutions; thesewere highly infective in two out of the three plates tested.

While carrying out the viral dilution tests, tests were also performedusing 2 ml of 3% ZnAc solution in distilled water mixed with 2 mlaliquots of undiluted viral stock. The zinc/virus mixtures wereincubated for 2 hours, diluted with RPMI at 1:100 and 1:1000 ratios, andmixed with lymphocytes for three hours; zinc concentrations were 27 and2.7 μg/ml. The cells were washed twice, inoculated into 12 well platesas described above, and cultured for 27 days. ELISA results are shown inFIG. 4. As shown, the 1:100 dilution (27 μg/ml Zn) completely preventedinfectivity, while the 1:1000 dilution (2.7 μg/ml) delayed the onset ofinfection.

EXAMPLE 10: HIV PRECIPITATION TESTS

Precipitation tests were also performed, using 2% ZnAc which was mixedwith an equal volume of undiluted viral stock, incubated for 24 hours,and centrifuged at 1500 rpm in a tabletop centrifuge for 5 minutes. Thesupernatant was sampled (100 μl) and serially diluted by medium, at 1:10followed by 2× dilutions (1:20, 1:40, 1:80, etc) to a maximum dilutionof 1:10240. Each dilution was analyzed spectrophotometrically todetermine the concentration of viruses suspended in solution. Aftersampling, each tube was hand-mixed and incubated for 24 hours. Thesolution near the top of the tube was sampled again, serially diluted,and tested using the ELISA assay. The tube was hand-mixed again,incubated for three more days, and sampled again to obtain Day 5 values.

The values for zinc-treated viruses averaged about 40% less than valuesfor identically diluted solutions that did not receive zinc treatment.This indicates that the zinc caused substantial precipitation of thevirus and lowered the concentration of free HIV particles in solution.

Thus, there has been shown and described a new and useful article ofmanufacture for reducing the risk of infection by sexually transmittedviruses, in people who were not previously infected. Although thisinvention has been exemplified for purposes of description andillustration by reference to certain specific embodiments, it will beapparent to those skilled in the art that various modifications andalterations of the illustrated examples are possible. Any suchequivalents which derive directly from the teachings herein, and whichdo not depart from the spirit and scope of the invention, are deemed tobe covered by this invention.

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We claim:
 1. An article of manufacture comprising an aqueous gelcontained within a watertight tube having a sealed first end, an outletorifice at an opposed second end, and at least one deformable plasticwall between said ends, wherein the aqueous gel is suitable for repeateddaily use as a genital lubricant during sexual intercourse and containsa selected water-soluble zinc salt, other than zinc sulfate, at aconcentration which inhibits at least one type of sexually transmittedvirus, wherein the tube is provided with a label indicating that theaqueous gel contained therein is to be applied to genital surfacesduring intercourse.
 2. The article of manufacture of claim 1 wherein thezinc salt is selected from the group consisting of zinc acetate, zincpropionate, zinc butyrate, zinc formate, zinc gluconate, zinc glycerate,zinc glycolate, and zinc lactate.
 3. The article of manufacture of claim1 wherein the deformable plastic wall of the watertight tube issufficiently thin to allow efficient transfer of heat from a surroundingglass or cup filled with warm water into the aqueous gel, therebyallowing the aqueous gel to be conveniently warmed before use byimmersing the plastic container in warm water, thereby promotingconsistent and reliable use of the aqueous gel during each act of sexualintercourse.
 4. An article of manufacture comprising an aqueous gelcontained within a watertight tube having a sealed first end, an outletorifice at an opposed second end, and at least one deformable plasticwall between said ends, wherein the aqueous gel is suitable for repeateddaily use as a genital lubricant during sexual intercourse and containsa selected water-soluble zinc salt, other than zinc sulfate, at aconcentration which inhibits at least one type of sexually transmittedvirus, wherein the tube is provided with a label indicating that theaqueous gel contained therein is effective as an anti-viral agentagainst at least one type of sexually transmitted virus.
 5. The articleof manufacture of claim 4 wherein the zinc salt is selected from thegroup consisting of zinc acetate, zinc propionate, zinc butyrate, zincformate, zinc gluconate, zinc glycerate, zinc glycolate, and zinclactate.
 6. The article of manufacture of claim 4 wherein the deformableplastic wall of the watertight tube is sufficiently thin to allowefficient transfer of heat from a surrounding glass or cup filled withwarm water into the aqueous gel, thereby allowing the aqueous gel to beconveniently warmed before use by immersing the plastic container inwarm water, thereby promoting consistent and reliable use of the aqueousgel during each act of sexual intercourse.